BOSTON -- A rare genetic variant may give clues for development of new therapeutic targets against Alzheimer's disease, researchers said here.

Action Points

Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Note that this genomic study demonstrated a relationship between a mutation that stabilizes amyloid precursor protein and protection against Alzheimer's disease.

Be aware that drugs that mimic the effect of this mutation (by reducing cleavage of APP) have begun to enter clinical trials.

BOSTON -- A rare genetic variant may give clues for development of new therapeutic targets against Alzheimer's disease, researchers said here.

In a study of 2,600 elderly Icelanders who underwent complete genomic sequencing, Thorlakar Jonsson, PhD, a research scientist at DeCode Genetics, an Amgen subsidiary based in Reykjavik, determined that about 0.45% of the island nation's population harbors the mutation in the Amyloid Precursor Protein gene known as A673T.

The genetic variation is found mainly in peoples of Scandinavia -- 0.51% of the population in Finland, 0.42% in Sweden and 0.21% in Norway, Jonsson said in his oral presentation at the annual Alzheimer's Association International Conference. An estimated 0.01% of the U.S. population also harbors the gene, he said.

There are 10 known cases in which individuals with A673T developed Alzheimer's disease, Jonsson said. Nine were from Jonsson's Icelandic database of the nation's nursing homes. The average age at death among those individuals was 88 years -- including four individuals who died at ages 95, 98, 100, and 101. Another report of one case involved a person with the mutation who developed Alzheimer's disease at age 89, he noted.

Jonsson also cited a case in which a Finnish patient died at age 104.8 years with little beta-amyloid pathology.

"These cases suggest that the variant delays the onset of Alzheimer's disease," he said, but may not prevent the disease. "A673T may, through its effect on the Amyloid Precursor Protein as a BACE1 substrate, shift the curve of normal cognitive decline, thus delaying Alzheimer's disease onset."

"Therapeutic effects that mimic the effect of A673T may be fruitful," Jonsson said.

Heather Snyder, PhD, director of medical and scientific operations for the Chicago-based Alzheimer's Association, said the research by the Icelandic team "underscores how basic science can help in the development of better drugs for the treatment of Alzheimer's disease."

She told MedPage Today, "As the researcher noted, there have been cases of Alzheimer's disease in patients who have been identified as having the A673T variant, so we can't be sure if a person with the variant will be able to delay the onset of Alzheimer's disease until late in life, or if the variant is actually protective against the disease."

Jonsson and his team of researchers scoured the nursing home database in Iceland. "We identified several coding variants in the Amyloid Precursor Protein. We imputed these variants into the genomes of patients with Alzheimer's disease and control participants and then tested [them] for an association with Alzheimer's disease," he reported.

"To our knowledge, A673T represents the first example of a sequence variant conferring strong protection against Alzheimer's disease," Jonsson said. The researchers estimated that the mutation results in an approximately 40% reduction in the formation of amyloidogenic peptides in vitro.

However, Jonsson cautioned that the protective effect of mutations in the Amyloid Precursor Protein is very specific. For, example, the A673V mutation confers virtually no protection at all against the disease.

"The strong protective effect of the A673T substitution against Alzheimer's disease provides proof of principle for the hypothesis that reducing the beta-cleavage of Amyloid Precursor Protein may protect against the disease," Jonsson said. Several pharmaceutical companies are pursuing medication based on BACE-1 inhibitors.

Jonsson is an employee of DeCode Genetics.

Snyder had no disclosures.

Reviewed by F. Perry Wilson, MD, MSCE Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner